The gold standard for the treatment of severe peripheral artery disease remains bypass grafting with autologous vein. However, when vein is not available, prosthetic grafts must be utilized and are associated with very high failure rates, approaching 70% at just 3 years. The primary cause of long-term failure of prosthetic grafts is development of neointimal hyperplasia. It is well established that nitric oxide (NO) is a potent inhibitor of neointimal hyperplasia. The two main classes of NO donors that have been used to inhibit neointimal hyperplasia locally are diazeniumdiolates and S-nitrosothiols (RSNO). Of these two, RSNO are present in human plasma and act as a NO reservoir since they can release NO and be regenerated back to RSNO. One mechanism by which NO is readily released from RSNO is through reduction by L-ascorbic-acid (AA). We envisioned creating a modified prosthetic graft that exploits this mechanism and taps into the potentially limitless endogenous supply of NO. Using a citric acid-based biocompatible polymeric material, poly (diol citrate) (POC), we developed an AA-POC-ePTFE vascular graft. Preliminary data have demonstrated prolonged generation of NO from these grafts upon contact with S-nitrosothiols in vitro. Thus, we hypothesize that an AA-POC-ePTFE graft will react with circulating RSNO and result in long-term NO generation at the blood-material interface in vivo and will inhibit the formation of neointimal hyperplasia as compared to traditional ePTFE grafts. To address this hypothesis, the specific aims of this proposal are as follows: 1) characterize and optimize the properties of the AA-POC-ePTFE grafts using an ex vivo perfusion circuit~ 2) develop and validate a guinea pig ePTFE bypass model~ and 3) evaluate the safety, biocompatibility, and efficacy of AA-POC-ePTFE grafts at generating NO and inhibiting neointimal hyperplasia in vivo. Currently, prosthetic grafts continue to be a poor substitute for autologous vein. There is a tremendous need for development of new biomaterials to address these inadequacies. Through a multidisciplinary collaboration, we developed an innovative vascular graft and confirmed prolonged NO generation in vitro. The studies described in this proposal will enable us to optimize this graft and investigate the safety and efficacy of this technology in vivo, hastening further preclinical investigation.